Process for the preparation of bicyclic compounds and the use of this process for the preparation of an ice inhibitor compound

ABSTRACT

A method for preparing compounds of formula (I)                    
     wherein R is selected from the group consisting of H. alkyl, aryl, and aralkyl of up to 18 carbon atoms and the amine function may be free or protected from a compound of formula (IA) wherein cyclization is carried out in a basic medium and in the presence of a phosphonic acid derivative and the use of said method as an intermediate step for preparing a compound inhibiting the interleukin-1 beta conversion enzyme.

This application is a 371 of PCT/FR00/00041 filed Jan. 11, 2000.

A subject of the present invention is a novel process for thepreparation of bicyclic compounds and the use of this process as anintermediate stage in the preparation of a compound which inhibits theinterleukin-1 beta converting enzyme (ICE).

The compound of formula (I) as defined below, in which R represents aterbutyl radical and the amine is protected in the form of phthalimido,is described in the Patent EP 94095. This compound of formula (I) isalso used for the preparation of the compound of formula (V) having aninhibitory activity on the interleukin-1 beta converting enzymedescribed in the International Application WO 97/22619.

One of the objectives of the invention is to find a novel process ofobtaining the compounds of formula (I).

Therefore a subject of the invention is a process for the preparation ofthe compounds of formula (I)

in which R represents a hydrogen atom, an alkyl, aryl or aralkyl radicalcontaining up to 18 carbon atoms and the amine function can be free orprotected, starting from a compound of formula (IA)

in which R has the same meaning as previously and the amine function canbe free or protected,

characterized in that the cyclization is carried out in a basic mediumand in the presence:

of a derivative of phosphonic acid of formula (P1):

P(═Z)(X¹)(X²)(X³)

in which Z is a sulphur or oxygen atom, X¹ represents a halogen atom, X²and X³, identical or different, represent a halogen atom, an alkyloxyradical containing 1 to 6 carbon atoms, an aryloxy radical containing 6to 12 carbon atoms or an arylalkyloxy radical containing 7 to 15 carbonatoms,

or of a trimer of formula (P2)

R preferably represents a hydrogen atom, a methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tertbutyl, benzyl, phenyl or naphthylradical and quite particularly methyl, ethyl and tertbutyl.

When the amine function is protected, the protection can be doneaccording to the standard methods known to a person skilled in the art.

The amine function can be protected in the form of an —NR¹R² radical inwhich

either R¹ represents a

radical, Ra, Rb, Rc and Rd representing an alkyl or aryl radicalcontaining up to 18 carbon atoms or a mono or polycyclic radicalcontaining one or more heteroatoms, X representing a hydrogen atom, analkyl radical containing up to 8 carbon atoms or an aryl radicalcontaining up to 14 carbon atoms, and R² represents a hydrogen atom,

or R¹ and R² together form a mono or polycyclic radical containing 1 ormore heteroatoms. The amine can thus be protected in the form of aphthalimido

or also in the form of the

radical.

Preferably, the amine is protected in the form of a phthalimido.

Among the derivatives of phosphonic acid of formula P(═Z)(X¹)(X²)(X³),it is in particular the following derivatives:

(Cl)P(O)(Ph)₂, (Cl)₂P(O)(OPh)₂, (Cl)P(O)(OEt)₂, (Cl)₂P(O)(OEt)₂, POCl₃,POBr₃ and P(S)Cl₃.

The cyclization reaction is preferably carried out in the presence ofPOCl₃ or POBr₃ and the base is in particular an organic base, forexample triethylamine, pyridine or 2,6-lutidine.

A more particular subject of the invention is the process as describedpreviously in which the trihalogenophosphonic acid is POCl₃.

A more particular subject of the invention is the process as describedpreviously in which the trihalogenophosphonic acid is POBr₃.

A more particular subject of the invention is the process as describedpreviously in which the base is chosen from pyridine or 2,6-lutidine.

A more particular subject of the invention is the process as definedpreviously characterized in that the cyclization temperature iscomprised between 70 and 80° C.

A more particular subject of the invention is the process as definedpreviously characterized in that the solvent is dichloroethane.

The compound of formula (IA) is in the form of a mixture of SS and SRdiastereoisomers or in the form of the SR diastereoisomer.

The compound of formula (I) is in the form of a mixture of SS and SRdiastereoisomers or in the form of the SR diastereoisomer.

A subject of the invention is also a process for the preparation of thecompound of formula (I) in racemic or optically active (Iopt) form,comprising the cyclization process as described above, and characterizedin that it comprises the following successive stages:

a) A compound of formula (II)

 in which R is as defined previously and Hal represents a halogen atom,is subjected to the action of a compound of formula (III)

 in which Aryl represents an aryl radical containing up to 14 carbonatoms, in order to obtain the compound of formula (IV)

 in the form of a mixture of S and R stereoisomers,

b) the compound of formula (IV) is subjected to the action of ananhydride of formula (F)

 the amine function being in protected or non-protected form, whilecarrying out a deprotection by hydrogenolysis, in order to obtain thecompound of formula (IA)

 as defined above,

c) the compound of formula (IA) is subjected to the action of aderivative of phosphonic acid (P1) or (P2) as defined above, in thepresence of a base, in order to obtain the compound of formula (I) asdefined above

d) if appropriate, the amine function is deprotected in order to obtainthe compound of formula (I) in which the amine function is notprotected,

e) if appropriate, the compound of formula (I) in the SS+SR or SR formis subjected to the action of a deracemization and/or epimerizationagent in order to obtain the compound of formula (Iopt) corresponding tothe SS diastereoisomer,

f) if appropriate, the amine function is deprotected in order to obtainthe compound of formula (Iopt) in which the amine function is notprotected.

In a preferred embodiment:

Hal represents a chlorine atom;

R represents an alkyl radical containing 1 to 4 carbon atoms;

Aryl represents a phenyl or naphthyl radical,

Compound (F) is N-phthaloyl-L-glutamic anhydride

The amine function of the compounds of formulae (IA), (I) or (Iopt) isin protected form and in particular in phthalimido form;

The reaction between the compounds of formula (II) and the compounds offormula (III) takes place in the presence of a base for example in thepresence of an alkaline carbonate such as potassium carbonate;

The deprotection by hydrogenolysis is carried out according to standardconditions known to a person skilled in the art, for example thehydrogenolysis agent is hydrogen in the presence of palladium on carbon;

The deracemization and/or epimerization agent is a base, more especiallya strong base, for example an alkaline or alkaline-earth alcoholate suchas sodium or potassium methylate, sodium or potassium terbutylate or alithiated amine such as LDA;

The action of a deprotection agent of the amine can be carried out inparticular by the action of a hydrazine.

A quite particular subject of the invention is the process as definedpreviously in which (F) is the anhydride of phthaloyl glutamic acid.

A quite particular subject of the invention is the process as definedpreviously in which the amine function of the compounds of formulae(IA), (I) or (Iopt) is protected in the form of a phthalimido group.

A quite particular subject of the invention is the process as definedpreviously in which, within the compounds of formula (II), (IV), (IA),(I) and (Iopt), R is a methyl, ethyl or tertbutyl radical.

A quite particular subject of the invention is the process as definedpreviously in which the compound of formula (I) is ethyl9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate:

A quite particular subject of the invention is the process as definedpreviously in which the compound of formula (Iopt) isethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate:

The compounds of formula (I) can in general be used for the synthesis ofmedicaments as indicated in the Patent EP 94095. The compounds offormulae (II) and (III) and (F) are known and can be prepared accordingto the experimental method described below.

A subject of the invention is also the use of the process as definedabove as an intermediary stage for the preparation of a compound offormula (V)

via the compound of formula (Iopt) as defined previously, characterizedin that this process comprises the stages of the process for thepreparation of the compounds of formula (Iopt) starting from thecompounds of formula (II) as defined previously.

A subject of the invention is also the use as defined above,characterized in that the compound of formula (Iopt) is ethyl(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate

A subject of the invention is also the use of the process as definedabove as an intermediate stage of the overall preparation process forthe compounds of formula (I) and (Iopt) as defined previously.

Finally, a subject of the invention, as an intermediate compound, is thecompound of formula (IA) as defined previously.

The following examples illustrate the invention without however limitingit.

Preparation 1

Preparation of bis(phenylmethyl) 1,2-hydrazinecarboxylate

1.5 liters of methanol and 25 g of hydrazine monohydrate at 80% areplaced under nitrogen. The reaction medium is cooled down to 0° C. andthen 75 g of benzyl chloroformate and a solution of 93 g of sodiumcarbonate in 1100 ml of demineralized water are introduced. The reactionmixture is maintained at 0° C. for 1 hour, followed by separating andwashing by displacement with a mixture of 100 ml of methanol and 100 mlof water, then washing by displacement with 500 ml of water at 0° C.After drying 107.6 g of sought product is obtained.

Preparation 2

Preparation of N-phthaloyl-L-glutamic Anhydride D (+)

2-tetrahydro-2,6-dioxo-2H-pyran-3-yl-1H-isoindole-1,3(2H)-dione (R)

Stage a: N-phthaloyl-L-glutamic Acid

2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-pentanedioic acid (2S)

10 g of L-glutamic acid then 16 g of N-carbethoxyphthalimide (Nefkensreagent, commercial) are added to a solution of 14.4 g of sodiumcarbonate in 180 ml of water. Agitation is carried out at ambienttemperature for 2 hours followed by extraction with ethyl acetate. Theorganic phase is evaporated under reduced pressure until a dry extractis obtained and 2.74 g of crude product is obtained. Washing is carriedout with sodium bicarbonate, then after returning to the acid andextraction with ethyl acetate, 370 mg of expected product and H₂N—CO₂Etare isolated. Moreover, the aqueous phase is adjusted to pH=2 with 36%hydrochloric acid at a temperature lower than 5° C. then extracted withethyl acetate, washed with a saturated solution of sodium chloride,dried, filtered and concentrated under reduced pressure until 22.7 g ofexpected product is obtained in the form of an oil.

Mass spectrum (M−H)⁻=276⁻

Infrared (Nujol): 1775 cm⁻¹(m), 1720 cm⁻¹ (F, complex): CO 1611 cm⁻¹:Aromatic

Stage b:

160 ml of tetrahydrofuran is added and 18.6 g of DCC(1,3-Dicyclohexyl-carbodiimide) in solution in 55 ml of tetrahydrofuranis added dropwise over 30 minutes to the product obtained in stage a).Agitation is carried out for 1 hour at 15-17° C., followed by filtering,rinsing with tetrahydrofuran, evaporating under reduced pressure until adry extract is obtained which is taken up in isopropyl oxide. Afteragitation for 30 minutes, filtering is carried out followed by washingand drying. 14.98 g of expected product is obtained.

α_(D)=−52.63

¹H NMR (DMSO) 2.12 (m, 1H); 2.61 (m, 1H); 2.98 (dm, 1H); 3.16 (ddd, 1H);5.48 (dd, 1H); 7.82 (m, >4H)

EXAMPLE 1 Ethyl(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate

Stage a: Preparation of 2,5-dibromopentanoic Acid

39 ml of bromine is added to a mixture of 106 g of 5-bromopentanoic acidand 1 ml of phosphorus tribromide. The reaction mixture is taken to70-80° C. for 16 hours 30 minutes. The reaction medium is taken to 100°C. for 15 minutes and allowed to return to ambient temperature. 147 g ofsought product is obtained.

Stage b: Preparation of Ethyl 2,5-dibromopentanoate

24.37 g of oxalyl chloride is added to a mixture containing 50 g of theacid prepared in the previous stage, 15 drops of dimethylformamide and300 ml of dichloromethane. The reaction mixture is maintained underagitation, at ambient temperature, until the reaction is complete. Thereaction mixture is cooled down to 10° C. and 50 ml of ethyl alcohol isadded. Agitation is carried out for 30 minutes at 10° C., the reactionmedium is left to return to ambient temperature and agitation is carriedout for 3 hours at ambient temperature, followed by bringing to drynessand the sought product is obtained.

Stage c: Cyclization

Preparation of 3-ethyl-1,2-bis(phenylmethyl)(S)-tetrahydro-1,2,3-pyridazinetricarboxylate and3-ethyl-1,2-bis(phenylmethyl)(R)-tetrahydro-1,2,3-pyridazine-tricarboxylate

A suspension of 12.1 g of ethyl 2,5-dibromopentanoate (Stage b) in 50 mlof diglyme is introduced at 20-25° C. into a suspension containing 10.42g of bis(phenylmethyl) 1,2-hydrazine-carboxylate (Preparation 1), 65 mlof diglyme and 8.26 g of potassium carbonate. The suspension obtained isheated at 90° C. and agitation is maintained for 48 hours, followed bycooling down to 20° C., pouring into a solution containing 50 ml of 2Nhydrochloric acid and 150 ml of a mixture of water and ice. Extractionis carried out with ethyl acetate, followed by washing with water,drying, filtering, rinsing with ethyl acetate and drying. Finally, thecrude product is purified by chromatography on silica eluting with aheptane/ethyl acetate mixture 40/20 and 10.71 g of sought product isobtained.

Stage d: Acylation and Hydrogenolysis

Preparation of(1S)-[3-oxo-3-(tetrahydro-3-ethoxycarbonyl-1(2H)-pyridazinyl)propyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2-aceticAcid α,

The mixture constituted by 15 g of3-ethyl-1,2-bis(phenylmethyl)tetrahydro-1,2,3-pyridazinetricarboxylatein the form of an R+S mixture as prepared in Stage c, 150 ml oftetrahydrofuran, 2.5 g of palladium on carbon (10%) and 9.08 g ofphthaloyl glutamic acid anhydride as prepared according to Preparation 2is placed under hydrogen pressure (1.3 bar) for 24 hours. Afterfiltration, evaporation under reduced pressure is carried out until adry extract is obtained which is taken up in 100 ml of ethyl acetate and150 ml of a saturated solution of sodium bicarbonate. Extraction iscarried out 3 times and the bicarbonate solution is acidified to pH=3with 36% hydrochloric acid. Extraction is carried out 3 times withdichloromethane followed by washing with water. 13.16 g of crude productis obtained which is purified by chromatography on silica eluting with atoluene/ethyl acetate/acetic acid mixture 20/80/1.5 in order to obtain12.7 g of expected product.

NMR (250 Hz, CDCl₃): 1.24 (d, 3H, OCH₂CH ₃); 4.12 (q, 2H, OCH ₂CH₃);4.36-4.40 (m, 1H, H1 in position alpha or beta); 4.69-4.92 (m, 1H, H9 inposition alpha); 7.70-7.86 aromatic H's.

Stage e1: Cyclization with POCl₃

ethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate.

ethyl-(1R-trans)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate.

The following solutions A and B:

A: 417 mg of the ester prepared in Stage d in 4 ml of dichloroethane towhich 1 ml of a solution of 1.2 ml of 2,6-lutidine in 5 ml ofdichloroethane has been added.

B: 1 ml of a solution of 1.9 ml of POCl₃ in 10 ml of dichloroethane, areadded over 3 hours and simultaneously to a solution of 20 ml ofdichloroethane heated beforehand to 75° C., then agitation is carriedout for 1 hour at this temperature. The reaction medium is cooled downto 10° C., demineralized water is added, followed by extraction withdichloromethane and evaporation under reduced pressure in order toobtain a crude product (0.415 g) which is purified by chromatography onsilica eluting with a heptane/dichloromethane-/ethyl acetate mixture1/1/1. 161.8 mg of the SS diastereoisomer, 126.7 mg of the SRdiastereoisomer and 5.8 mg of an SS+SR mixture are isolated.

Stage e2: Cyclization with POBr₃

ethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate.

ethyl-(1R-trans)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate.

The following solutions A and B:

A: 417 mg of the ester prepared in Stage d in 4 ml of dichloroethane towhich 1 ml of a solution of 2.4 ml of 2,6-lutidine in 10 ml ofdichloroethane has been added.

B: 1 ml of a solution of 5.85 g of POBr₃ in 10 ml of dichloroethane, areadded over 3 hours and simultaneously to a solution of 20 ml ofdichloroethane heated beforehand to 80° C., then agitation is carriedout for 1 hour to this temperature. The reaction medium is cooled down10° C., demineralized water is added, followed by extraction withdichloromethane and evaporation under reduced pressure in order toobtain a crude product (0.419 g) which is purified by chromatography onsilica eluting with a heptane/dichloromethane/ethyl acetate mixture1/1/1. 163 mg of the SS diastereoisomer, 143 mg of the SRdiastereoisomer and 6.2 mg of an SS+SR mixture are isolated.

Stage f: Deracemization/epimerization

ethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate.

A solution containing 0.029 g of potassium terbutylate and 0.3 ml ofdimethylformamide is introduced at a temperature of −45/−48° C. over onehour 30 minutes into a mixture containing 0.194 g of the SS+SR mixtureprepared in Stage d, 1.5 ml of dimethylformamide and 0.75 ml ofterbutanol. The mixture is maintained under agitation for 1 hour andafter cooling down to −50° C., 0.4 g of ammonium chloride in powder formis introduced. Agitation is carried out for 10 minutes at −45° C., 1 mlof ammonium chloride is added at 20° C. and agitation is carried outagain for 10 minutes. After 5 minutes, 2 ml of demineralized water isadded, followed by extraction with ethyl acetate, washing withdemineralized water, decanting, concentrating and drying. 0.166 g of theexpected SS diastereoisomer is obtained.

α_(d)=−75.3° (1% in methanol)

NMR (250 Hz, CDCl₃): 1.73 (m, 3H, H-2alpha H-3alpha H-3beta; 1.24 (d,3H, OCH₂CH ₃); 2.38 (m, 3H, H2beta, H7alpha, H8alpha); 2.92 (m, 1H,H4alpha); 3.39-3.44 (m, 1H, H8beta); 3.62(m, 1H, H7beta); 4.23 (m, 2H,OCH ₂CH₃); 4.66-4.71 (m, 1H, H4 in position beta); 5.26-5.41 (m, 2H, H1and H9 in position alpha); 7.72-7.88 aromatic H's.

What is claimed is:
 1. A process for the preparation of a compound ofthe formula

wherein R is selected from the group consisting of hydrogen, and alkyl,aryl and aralkyl up to 18 carbon atoms and the amine function can befree or protected comprising cyclizing a compound of the formula

wherein R has the above meaning and the amine function can be free orprotected in a basic medium and in the presence: of a derivative ofphosphonic acid of the formula P(—Z)(X¹)(X²)(X³)  P₁ wherein Z is asulfur or oxygen, X¹ is halogen, X² and X³ are individually selectedfrom the group consisting of halogen, alkoxy, of 1 to 6 carbon atoms,aryloxy of 6 to 12 carbon atoms and arylalkoxy of 7 to 15 carbon atoms,or of a trimer of the formula


2. The process of claim 1 wherein (P1) is POCl₃.
 3. The process of claim1 wherein (P1) is POBr₃.
 4. The process of claim 1 wherein the base ispyridine or 2,6-lutidine.
 5. The process of claim 1 wherein thecyclization temperature is between 70 and 80° C.
 6. The process of claim1 wherein the solvent is dichloroethane.
 7. A process for thepreparation of a compound of formula (I) in racemic or optically active(Iopt) form, comprising a) reacting a compound of the formula

 wherein R is selected from the group consisting of hydrogen and alkyl,aryl and aralkyl of up to 18 carbon atoms and Hal is halogen with acompound of the formula

 wherein Aryl is aryl of up to 14 carbon atoms, to obtain a compound ofthe formula

 in the form of a mixture of R and S stereoisomers b) reacting acompound of formula (IV) with an anhydride of the formula

 with the amine function being protected or non-protected while carryingout a deprotection by hydrogenolysis to obtain a compound of the formula

c) reacting a compound of formula (IA) with a derivative of phosphonicacid (P1) or (P2) of claim 1 in the presence of a base to obtain acompound of the formula

d) optionally, the amine function is deprotected to obtain a compound offormula (I) in which the amine function is not protected, e) optionally,the compound of formula (I) in the SS+SR or SR form is reacted with aderacemization and/or epimerization agent to obtain the compound offormula (Iopt) corresponding to the SS diastereoisomer,

f) and optionally, the amine function is deprotected to obtain acompound of formula (Iopt) in which the amine function is not protected,g) The process of claim 7 wherein F is N-phthaloyl-L-glutamic anhydrideof the formula


8. Process as defined in claim 7 in which F is N-phthaloyl-L-glutamicanhydride:


9. The process of claim 1 wherein the amine function of the compounds offormulae (IA), (I) and (Iopt) is protected in phthalimido form.
 10. Theprocess of claim 1 wherein R is methyl or ethyl or tertbutyl.
 11. Theprocess of claim 1 wherein the compound of formula (I) isethyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate


12. The process of claim 1 wherein the compound of formula (Iopt) isethyl-(1S-cis)-9-(1,3-dihydro-1,3-dioxo-2IIisoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino-[1,2-a][1,2]diazepine-1-carboxylate:


13. A compound of the formula

wherein R is selected from the group consisting of hydrogen, alkyl of 1to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and theamine group is free or protected.